Breast cancer is known from ancient time,and the treatment strategy evolved as our understanding of the disease changed with time. In 460 BC Hippocrates described breast cancer as a humoral disease and presently after a lot of studies breast cancer is considered as a local disease with systemic roots. For most of the twentieth century Halsted radical mastectomy was the "established and standardized operation for cancer of the breast in all stages, early or late". New information about tumor biology and its behavior suggested that less radical surgery might be just as effective as the more extensive one. Eventually, with the use of adjuvant therapy likeradiation and systemic therapy, the extent of surgical resection in the breast and axilla got reduced further and led to an era of breast conservation. The radiation treatment of breast cancer has evolved from 2D to 3D Conformal and to accelarated partial breast irradiation, aiming to reduce normal tissue toxicity and overall treatment time. Systemic therapy in the form of hormone therapy, chemotherapy and biological agents is now a well-established modality in treatment of breast cancer. The current perspective of breast cancer management is based on the rapidly evolving and increasingly integrated study on the genetic, molecular , biochemical and cellular basis of disease. The challenge for the future is to take advantage of this knowledge for the prediction of therapeutic outcome and develop therapies and rapidly apply more novel biologic therapeutics.

Breast cancer is a heterogeneous disease representing a broad spectrum of biologic potential. Surgery is the oldest method of treatment. However, a variety of medical therapies have also been described. Progress in breast cancer management rests on a multidisciplinary team effort involving basic researchers, radiologists, pathologists, surgeons, radiation oncologists, medical oncologists and psychologists. All these disciplines have gradually evolved and contributed towards improved management in one of the three areas i.e. locally in breast, regional draining lymph nodes, and in systemic manifestation.

History

Breast cancer is an ancient disease. It has been mentioned in almost every period of recorded history. Ancient Egyptians were the first to note the disease more than 3,500 years ago. [1] The earliest record of breast cancer comes from Edwin Smith surgical papyrus (Egyptian time 3000-2500 BC) which describes eight cases of breast cancer, admitting that there was no treatment. However, one case was reported tohave been treated by cauterization with a fire stick. Writings from India dating 2000 BC do mention the treatment of breast cancer with surgical excision, cautery and arsenic compound. In 460 BC, Hippocrates, the father of Western Medicine, described breast cancer as a humoral disease. Galen (AD 131-203) attributed breast cancer to an excess of black bile in the body or a particular humor that prevails in the body (systemic concept). Towards the end of the sixteenth century, new techniques were introduced to surgery. Vesalius (1514-64) used ligatures, Guillemeau (1550-1601) advocated removal of the pectoral muscle along with the breast. Severinus (1580-1659) advocated removal of axillary nodes along with the breast as he appreciated that axillary nodes are part of the malignant process. Descartes (1596-1650) proposed a lymph theory of origin, which was perpetuated by John Hunter (1728-93), this was conceptually better than the black bile theory and encouraged more and more surgeons to remove the obviously affected lymph nodes. In 1757 a French surgeon Henry LeDran advanced the theory that breast cancer at its earliest stage is local disease then spreads to lymph nodes and then enters the circulation. This theory offered the hope that surgery might cure the disease if performed early. Other surgeons also embraced this concept. In 1871, Henry Arnott also reiterated the local origin of breast cancer and advocated the principle of curative surgery with en-bloc operation at the earliest moment.

Surgery

The Halsted radical mastectomy approach was begun at the Johns Hopkins Hospital in Baltimore in 1882. The operation involved an extensive resection of the skin and breast tissue, underlying pectoralis major and minor muscles with Level I to III axillary lymph nodes. This radical surgical approach reduced the local recurrence rate to 6%from the prevailing 51-82% at that time. [2] This radical operation resulted in a gross deformity and in frequent problems of lymphedema and sensory abnormalities of the arm and chest. By 1912, surgeons led by J. B. Murphy [3] discontinued removal of the pectoralis muscles due to lack of substantial recurrences in the muscle. Patey [4] in 1948 also substantiated the modified radical approach. The American College of Surgeons [5] in 1976 conducted a survey that indicated that radical mastectomy was still employed in 20%of the 6793 patients reviewed. Just five years later a similar survey [6] revealed that the radical mastectomy approach was being used in only 3.4% of breast cancer patients. The report of McWhirter [7] in 1948 began the transition to breast conservation and addition of adjuvant radiation therapy. Fisher and his colleagues [8],[9] in a large prospectivelyrandomized study, proved the effectiveness of lessthancomplete removal of breast tissue and axillary lymph nodes. The publication of these data [9] in 1989 established the move toward less radical surgery and provided the rationale that many patients could be treated surgically with preservation of an essentially normal breast. Nowadays surgical management of patients with operable breast cancer addresses both the primary tumor and regional lymphatics. The primary tumor may be managed by mastectomy or lumpectomy and the nodal regions may be surgically addressed by lymph node dissection or sentinel lymph node biopsy. For locally advanced breast cancer neoadjuvant chemotherapy is the first step to reduce the bulk of the disease followed by breast conservation therapy or modified radical mastectomy(MRM) depending on the clinical situation.

Radiation therapy

By the beginning of the twentieth century radiotherapy had been shown to be effective in treating breast cancer. In 1932, Pfahler [10] from the United States reported the use of radiotherapy in 1022 patients with breast cancer, of whom 53 had early disease, and who had refused or were too frail for surgery. The fiveyear survival of patients with early disease was 80% and even patients with Stage II disease fared better than historical controls. In 1937 Keynes, a surgeon at St Bartholomew's Hospital in London described the results of conservative treatment of breast cancer using implanted radium needles. [11] Five-year survival was 71% in patients with Stage I disease and 29% in patients with Stage II disease. These results appeared to be as good as those achieved by radical mastectomy, but despite this, the technique was not widely used due to the limited availability of radium, handling problems and post-radiation fibrosis. Robert McWhirter [7] was the foremost proponent of radiotherapy in the mid-twentieth century and he reported the results of simple mastectomy followed by radiotherapy to the supraclavicular, internal mammary and axillary lymph nodes in 759 patients. The five-year survival rate of 62% was comparable to that achieved by standard radical mastectomy, implying that radiotherapy was effective in treating nodal disease. In France, Baclesse [12] had clearly realized by the 1940s that most breast cancers were responsive to radiation, and also that the tumor size was critically important in determining the likelihood of local control. The first randomized controlled trial of conservative surgery and radiotherapy versus radical mastectomy was performed at Guy's Hospital in London by Atkins etal., in 1972. [13] Fisher and his colleagues [8],[9] in a large prospectively randomized study, proved that breast conservation therapy with radiation is equally effective as radical breast surgery. The importance of local control and its effect on survival has been highlighted by the results of three published studies, the Danish study [14] of high-risk premenopausal women, the Canadian study [15] and the third Danish study. [16] These studies have highlighted the importance of local control on survival and suggest that micro metastases in locoregional lymphatics are a potent source of systemic metastases. They also suggest that eradication of locoregional metastases improves survival. The radiation treatment of breast cancer has evolved from 2D to 3D Conformal Radiotherapy (3DCRT) and to accelerated partial breast irradiation (APBI), aiming to reduce normal tissue toxicity and overall treatment time. There has been growing interest in APBI and various approaches have been developed under Phase I-III clinical studies; these include Multicatheter Interstitial Brachytherapy, Balloon Catheter Brachytherapy, Conformal External Beam Radiation Therapy and Intraoperative Radiation Therapy (IORT).

The standard radiation treatment as per current practice is to deliver radiation (2-dimensional/3-dimensional/intensity modulated radiation therapy(IMRT to chest wall after MRM, radiation to intact breast after breast conservation therapy. Palliative RT is used in advanced breast lesions for palliation of symptoms.

Systemic therapy

There are three main modalities of effective systemic medical therapy for breast cancer. The oldest one is endocrine therapy (ET) for patients whose tumors express estrogen and/or progesterone receptors, which account for about two-thirds of breast cancer patients; the second is chemotherapy (CT) and finally, biological therapy (BT), which includes a growing list of new agents directed against molecular targets in the cancer cell and its environment, the role of which is currently being evaluated.

Hormone therapy

By the end of the nineteenth century, Thomas Beatson [17] had demonstrated that breast cancer is hormonally dependent in at least a proportion of patients, by observing tumor regression in two of the metastatic breast cancer patients after surgical oophorectomy. The hormonal importance was subsequently confirmed by use of adrenelectomy [18] and hypophysectomy. [19] The scientific foundation of hormone dependence was confirmed by the discovery of the estrogen receptor in breast tumor. Thereafter over a period of time ablative endocrine surgery has now largely been replaced by development of Medical Endocrine Therapies. The estrogen antagonist tamoxifen has mostly replaced surgical oophorectomy. Aromatase inhibitors which block peripheral synthesis of estrogen have replaced adrenelectomy, and luteinizing hormone-releasing hormoneLHRH agonists have replaced hypophysectomy. Hormone receptor (estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2) status identify key molecular subtypes of human breast tumors and currently guide choice of therapy. For patients with hormone-receptor positive (ER,PR-positive) breast cancer, hormone therapy with tamoxifen and aromatase inhibitors (anastrozole, letrozole, exemestane) or ovarian suppression (in premenopausal patients) represent the backbone of treatment, along with chemotherapy. For patients with HER2-positive breast cancer, regardless of any other characteristics, the introduction of anti-HER2 targeted agents has dramatically improved prognosis. [20] A new hormonal agent Fulvestrant is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer which has progressed following prior endocrine therapy. [21]

Chemotherapy

The introduction of chemotherapy in the fifth and sixth decades of the twentieth century has resulted in the development of curative therapeutic interventions for patients with several types of advanced solid tumors and hematologic neoplasms. In breast cancer initially single-agent chemotherapy was used in hormone-resistant metastatic setting. The chemotherapeutic agents were cyclophosphamide, phenylalanine mustard, vincristine, vinblastine, methotrexate and 5-fluorouracil. Response rates had ranged from 0-38%. The first combination chemotherapy was Cooper's regimen. [22] Using the large case series of breast cancer patients available at the Milan Cancer Institute, Bonadonna [23],[24] introduced the CMF protocol (Cyclophosphamide-Methotrexate-5-Fluorouracil). In 1976, Bonadonna etal.,[25] presented the first report on the efficacy of CMF as adjuvant treatment for node-positive breast cancer. The ease of administration and the virtual absence of severe acute toxicity made CMF the most frequently used combination of drugs in clinical practice in oncology. Although CMF regimen represented the gold standard in the 1970s, anthracycline-based regimens have become the mainstay of adjuvant chemotherapy for early breast cancer since the 1990s. A review by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) published in 2005, [26] showed that anthracycline-containing regimens reduced the annual breast cancer death rate by 38% for patients under the age of 50 years and by 20% for those aged between 50 to 69 years. The incorporation of a taxane into an anthracycline-based regimen has demonstrated further benefit in the treatment of early-stage breast cancer. The Cancer and Leukemia Group (CALGB) 9344 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 were pivotal trials establishing the efficacy of four cycles of paclitaxel given after four cycles of doxorubicin plus cyclophosphamide (AC) in patients with node-positive disease. [27] The Breast Cancer International Research Group (BCIRG) 001 demonstrated superior disease-free survival and overall survival when Docetaxel was given concurrently with Doxorubicin and Cyclophosphamide (TAC) compared with 5-Fluorouracil, Doxorubicin, and Cyclophosphamide (FAC) in patients with node-positive breast cancer. [28] These first-generation taxane trials were practice-changing, clearly establishing the benefit of this class of agents in the treatment of early-stage breast cancer. Presently, cancer chemotherapy is used in neoadjuvant, adjuvant and in metastatic settings.

Targeted therapy

Targeted therapeutic agents selectively inhibit the various mechanisms by which cancer cells grow, invade and metastasize. These mechanisms include self-sufficiency in growth signals, evasion from apoptosis, continuous replicative potential, angiogenesis, and stromal invasion with the development of metastases. The introduction of the bcr/abl Tyrosine Kinase Inhibitor (TKI) Imatinib represented a hypothesis-generating change of treatment paradigm, proving the efficacy of targeted therapy in diseases that are crucially dependent upon the uninhibited function of the relevant target. Tamoxifen was the first, used as a targeted therapy in breast cancer management. After that, development of Trastuzumab a recombinant humanized monoclonal antibody that interferes with HER-2/neu protein, has been a significant cornerstone. HER-2 over-expression is observed in 20-25% of all breast cancer patients and is directly linked to deregulated activation of the intracellular mitogenic signaling, leading to aggressive tumor behavior. [29] Another important target in cancer in general, and breast cancer in particular, is the vascular endothelial growth factor (VEGF) receptor family that plays an essential role in angiogenesis, and therefore, in cancer metastases. [30] The principal agent targeting VEGF is a monoclonal antibody called Bevacizumab. Bevacizumab, was approved in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the results of ECOG 2100, in which the addition of Bevacizumab improved the response rate and doubled progression-free survival (PFS) compared with treatment with paclitaxel alone. [31] Monoclonal antibodies such as Trastuzumab and Bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and theVEGF antagonists have shown synergism with a broad spectrum of established chemotherapeutic agents, thus being approved for first-line treatment of metastatic breast cancer in combination with taxanes. As a next step, TKIs have been integrated into daily routine as an alternative approach for targeting HER2. The dual HER1/2 inhibitor Lapatinib demonstrated activity in trastuzumab-pretreated metastatic breast cancer patients in combination with capecitabine. [32] Recently published data indicate that a combination of two biological agents such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab-related progression. [33],[34] PARP inhibitors (poly ADP-ribose polymerase inhibition), mediated by a new class of small molecules, is an interesting area of investigation. [35],[36] Future directions of research in HER2-positive breast cancer should focus on the evaluation of novel antibodies (pertuzumab, T-DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt), and of receptor cross-talk between estrogen receptor and insulin-like growth factor (IGFR).

» Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is defined as tumors that are negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). [37] TNBC is difficult to treat and a biologically aggressive disease with limited treatment options. However, a subset of patients with triple-negative tumors may respond to chemotherapy. Therefore, optimization of chemotherapy regimens is required in treating TNBC. Taxane-based regimens are the only ones where Level 1 evidence is available. The emerging treatment approach is the use of epothilones. The epothilones are a group of novel microtubule-stabilizing agents with demonstrated activity in TNBC and ongoing trials are evaluating the combination of epothilones with targeted agents or inclusion of epothilones in novel combination regimens. The ixabepilone, a novel semi-synthetic epothilone B analogue is an effective therapeutic option for patients with TNBC. [38],[39] The combination of ixabepilone and capecitabine is clinically superior to capecitabine alone in patients with taxane-sensitive or taxane-resistant ER-negative tumors. [40] Interesting new treatment options include the PARP inhibitors, which are currently in clinical trials for TNBC. [35],[36]

» Metastatic Breast Cancer

Compared with early-stage breast cancer, there are few proven standards of care for the management of metastatic breast cancer (MBC). For hormone receptor-positive MBC, endocrine therapy is the preferred option except if clinically aggressive disease mandates a quicker response or if resistance is suspected. The choice of endocrine agent should be individualized according to the patient's safety profile, co-morbidities and tumor biology. Tamoxifen with ovarian ablation is typically recommended for premenopausal patients, while third-generation aromatase inhibitors are advised for postmenopausal patients. HER2/neu-positive breast cancer patients should be treated with trastuzumab (Herceptin) with/without chemotherapy. [41] Among newer agents lapatinib may also be used and has shown a significant increase in time to progression in combination with capecitabine in patients progressing after trastuzumab. Preference is given to the sequential use of a single cytotoxic agent, as it is associated with reduced toxicity and improved quality of life in comparison with combination chemotherapy. The duration and number of regimens should be tailored to each individual patient; however, high-dose chemotherapy should not be proposed. Presently, for MBC new techniques are emerging, which have the ability to detect disseminating tumor cells present at the single-cell level in the bone marrow and peripheral blood. [42] Although much success has been achieved with the detection of disseminating tumor cells in the bone marrow, efforts are now being directed towards the detection of circulating tumor cells (CTCs) in peripheral blood. [43]

Personalized management

The field of oncology has now entered an era of "personalized medicine" in which the goal is to individualize therapy so that maximal benefit may be achieved and unnecessary toxicity minimized. Because breast cancer is a heterogeneous disease, it is critical to select those patients who will benefit from adjuvant chemotherapy to reduce the risk of recurrence while identifying those who would not, sparing them from potential toxicities. The development of the Oncotype DX Gene expression assay is an example of such an individualized approach. The Oncotype DX 21-gene Recurrence Score (RS) was developed as both a prognostic and predictive tool in women with hormone receptor (HR)-positive disease. [44]

» Conclusion

Changing fashion in breast cancer management has reflected not only changes in the belief regarding its pathogenesis but also a growth in knowledge about the disease as well as related science and technology. The current perspective of breast cancer management is based on the integrated study of the genetic, molecular, biochemical and cellular basis of breast cancer. Despite these advances, however, many women will develop disease recurrence and ultimately succumb to metastatic disease. Conversely, many women will be treated with adjuvant therapy for tumors that are destined to never recur. A greater understanding of the heterogeneity and molecular profiles of tumors will continue to inform the development of innovative targeted therapies that will lead to increased efficacy, decreased toxicities, and better selection of patients who will benefit from treatment. The challenge for the future is to take advantage of this knowledge for prediction of therapeutic outcome and develop therapies and rapidly apply more novel biologic therapeutics.

Wilson RE, Donegan WL, Mettlin C, Natarajan N, Smart CR, Murphy GP. The 1982 national survey of carcinoma of the breast in the United States by the American College of Surgeons. Surg Gynecol Obstet 1984;159:309-18. [PUBMED]

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717.